Studies of colon cancer using genetically engineered mice and chemical- carcinogen treated animals, epidemiological studies of human populations, and clinical intervention trials (with non-steroidal anti-inflammatory drugs; NSAIDS) all indicate that cyclooxygenase (COX) lies on the most common pathway to colon cancer. The participation of COX appears to occur at an early stage in the pathway-just after the loss of the second allele of APC. There are two forms of COX; one is found under basal conditions in many cells and tissue, while the other, COX-2, is usually expressed only in response to growth factors, tumor promoters, and cytokines. We and others have shown that COX-2 is expressed in adenomatous polyps and colon carcinoma, and that this results at least in part from constitutive transcription. One aim of this project is to define the mechanisms for the abnormal transcription, and in another aim to explore the hypothesis that there is post-transcriptional regulation as well. In the third aim, we will test whether over-expression of COX-2 (or COX-1) in intestinal epithelium is sufficient to cause polyps and cancer, and if it is synergistic with a high fat diet or the presence of other mutations commonly found in colon cancer (APC, p53). The mechanism by which prostaglandin synthase promotes colon carcinogenesis is not known-prostaglandins might stimulate proliferation or inhibit apoptosis. Additionally, this enzyme(s) can catalyze the oxidation of xenobiotics, which might have analogous actions. Finally, the reactions catalyzed by COX can generate mutagens. We will examine each of these mechanisms using transgenic mice, cell lines, and human tissues, and technical approaches from cell biology, molecular biology, and biochemistry. The observations that well studied, inexpensive drugs (NSAIDS) can decrease the incidence of colon polyps and cancer offers an exciting opportunity for chemoprevention. This proposal seeks to elucidate the mechanisms by which this effect occurs and should open new approaches to prevention of colon cancer.